© 2012 direct one communications, inc. all rights reserved. 1 the adopt trial and direct factor xa...

© 2012 Direct One Communications, Inc. All rights reserved. 1

The ADOPT Trial and Direct Factor Xa Inhibitors

Satyam Sarma, MD

Northwestern University Feinberg School of Medicine, Chicago, Illinois

A REPORT FROM THE 2011 SCIENTIFIC SESSIONS OF THE AMERICAN HEART ASSOCIATION


New Oral Anticoagulants

Over the past decade, new oral anticoagulants have been developed to overtake the mantle of heparin and vitamin K antagonist-based therapies.

Promising convenient fixed dosing, fewer food and drug interactions, improved side-effect profiles, and efficacy at least equal to that of warfarin, these compounds have revolutionized anticoagulant therapy by overcoming the unpredictability and dose variability of older treatment options.

Some of these novel agents have been studied clinically and have been used with varied success when compared with established therapy.1


Clinically Studied Novel Anticoagulants


Mechanism of Action

Compared with vitamin K antagonists such as warfarin, direct factor Xa and direct thrombin inhibitors target specific links in the coagulation chain to theoretically confer a more predictable dose-response relationship.

Direct factor Xa inhibitors (eg, rivaroxaban and apixaban) bind directly to the catalytic site of factor X in a 1:1 stoichiometric ratio.

Unlike indirect inhibitors, such as enoxaparin and fondaparinux, direct factor Xa inhibitors do not require antithrombin III as a mediating factor to exert their anticoagulant effects.1


Mechanism of Action

Direct thrombin inhibitors (eg, ximelagatran and dabigatran) block the effects of thrombin and limit the generation of fibrin from fibrinogen.

These drugs also affect the actions of thrombin on non-coagulation cascade pathways by inhibiting both thrombin-mediated platelet activation and activation of factors V, VIII, XI, and XIII.

Currently, dabigatran is the only oral direct thrombin inhibitor available for clinical use.1


Mechanism of Action

Considerable variability in the effective bioavailability of factor X and thrombin exists, affecting the in vivo actions of these drugs.

Factor Xa complexes with factor Va on the platelet surface to form the prothrombinase complex, increasing the catalytic activity of fibrin-bound factor Xa and allowing for highly efficient thrombin activation.26

Direct factor Xa and direct thrombin inhibitors can access the catalytic sites of their respective targets, whether in the circulation or in spatially confined locations such as a dense clot.


Measuring Plasma Anticoagulant Activity

Both prothrombin time (PT) and activated partial thromboplastin time (aPTT) rely on normal plasma concentrations of coagulation factors.

For direct inhibitors, routine measurement of PT and aPTT is not recommended, because these drugs may have unpredictable and unclear effects on assay results, depending upon their plasma concentration and dose timing.27

For dabigatran and rivaroxaban, aPTT may offer a qualitative measure of activity; normal levels suggest inadequate anticoagulant levels.28,29


Measuring Plasma Anticoagulant Activity

Prothrombin time results are more unreliable than aPTT measurements due to variability in the reagents used.

Thrombin time and activated factor Xa level are more direct measures of plasma anticoagulant activity for direct thrombin and direct factor Xa inhibitors, respectively, but their measurement is not readily available in most clinical laboratories.


Measuring Plasma Anticoagulant Activity Gray and Fareed30 compared the direct inhibitory

effects of direct factor Xa and direct thrombin inhibitors on thrombin activation, using an isolated tissue factor-activated prothrombin assay system.

In this assay, the inhibitory effects of rivaroxaban were most potent, followed by those of otamixaban, apixaban, melagatran, and dabigatran.

When assessed using traditional plasma-based assay systems, direct factor Xa inhibitors were less potent in altering PT and aPTT than were direct thrombin inhibitors, suggesting that their actions likely extend beyond simple inhibition of thrombin and factor Xa.


Anticoagulation Therapy for DVT and PE

Deep venous thrombosis (DVT) and pulmonary embolism (PE) are significant causes of morbidity and mortality in nonsurgical hospitalized patients, and the risk persists after discharge.

Anticoagulant therapy effectively prevents DVT and PE, has dramatically decreased mortality from PE in patients hospitalized for hip and knee surgery, and has become the standard of care.31

In addition, routine DVT prophylaxis during hospitalization has reduced the rates of DVT and fatal PE among patients who were hospitalized for medical illnesses and suffered a loss of mobility.32



A large number of patients suffer DVT and PE after hospital discharge, and few studies have assessed the efficacy of extending antithrombotic therapy into the postdischarge period in patients who had been hospitalized for medical illnesses.

A recent study of extended-duration prophylaxis of DVT in nonsurgical patients given subcutaneous enoxaparin for 28 days showed no significant net clinical benefit, due to an increase in bleeding that counterbalanced the decrease in the incidence of venous thromboembolism (VTE).33



Direct factor Xa and direct thrombin inhibitors offer the opportunity for a better prophylactic agent post discharge because they are given orally and have a more predictable dose response when compared with heparin or exoxaparin and vitamin K antagonist-based therapies.

Prior studies of novel oral anticoagulants in patients with atrial fibrillation showed a lower incidence of bleeding when compared with warfarin, and this benefit was expected to translate into a net clinical advantage for direct factor Xa and thrombin inhibitors in medically ill patients post discharge.


The ADOPT Trial: Background

The MAGELLAN study first examined extended-duration DVT prophylaxis using an oral factor Xa inhibitor and compared rivaroxaban given for 35 days with enoxaparin administered for 10 days post discharge.15

Patients treated with rivaroxaban had a decreased incidence of DVT and PE (4.4%) compared with 5.7% among patients receiving enoxaparin (relative risk [RR], 0.771; P = 0.0211).

However, the prophylactic benefits of rivaroxaban were substantially outweighed by an increase in bleeding rate (4.1% for rivaroxaban vs 1.7% for enoxaparin; RR, 2.5; P < 0.0001).


The ADOPT Trial: Background Apixaban, a direct factor Xa inhibitor, and

rivaroxaban share a number of similarities.

Apixaban has an oral bioavailability greater than 66%, compared with 80% for rivaroxaban, and a half-life of 8–13 hours, compared with 7–13 hours for rivaroxaban.34

In the ROCKET AF trial,12 rivaroxaban therapy was statistically noninferior to warfarin therapy, with the two drugs showing similar rates of major bleeding.

Results of selected clinical trials investigating the use of apixaban and/or rivaroxaban are summarized in the table on the following slide.12,14,17–19,35,36


Clinical Trials of Rivaroxaban and Apixaban


The ADOPT Trial: Background

The double-blind, double-dummy, placebo-controlled ADOPT trial compared the use of apixaban with enoxaparin therapy for preventing acute DVT and PE in medically ill patients following discharge from the hospital.16

Similar to the group conducting the MAGELLAN study, the ADOPT investigators hypothesized that prolonging VTE prophylaxis into the postdischarge period would prevent the occurrence of DVT or PE in patients at high risk.


The ADOPT Trial: Patients

For inclusion in this study, patients had to have been hospitalized for congestive heart failure (CHF) or acute respiratory failure, with an expected hospital stay of at least 3 days, or had to have been hospitalized for an infection, inflammatory bowel disorder, or acute rheumatic disorder and had a risk factor for VTE (age 75 years, body mass index > 30 kg/m², prior history of VTE or estrogen use).

Patients also had to have moderately (walking within the room) to severely limited (primarily bed-bound) mobility.


The ADOPT Trial: Patients

Patients were excluded if they had confirmed VTE; required anticoagulation for other indications; were on dual antiplatelet therapy; or had renal dysfunction, anemia (hemoglobin level < 9 mg/dL), abnormal liver function tests, or a high risk of bleeding.

Patients were randomized to receive either 2.5 mg of apixaban administered orally twice daily for 30 days or 40 mg of enoxaparin subcutaneously once daily for 6–14 days. Subjects randomized to the apixaban arm of the study received placebo injections of enoxaparin for at least 6 days to preserve blinding.


The ADOPT Trial: Outcome Measures

The primary efficacy outcome was a 30-day composite endpoint of:

» Death from VTE

» Fatal or nonfatal PE

» Symptomatic or asymptomatic VTE, as detected by lower extremity duplex sonography within the 30-day treatment period

Secondary endpoints included:

» Death from any cause within the 30- or 90-day study period

» A composite of death or the occurrence of VTE within the 6–14 days of enoxaparin therapy

» Symptomatic VTE or nonfatal PE within 60 days


The ADOPT Trial: Outcome Measures

The primary safety outcome was major bleeding, clinically relevant nonmajor bleeding, and all bleeding reported by investigators; MI; stroke; thrombocytopenia; and death from any cause.

Major bleeding was defined as fatal or overt if at least one of the following applied:

» A decrease in hemoglobin level of 2 g/dL over 24 hours

» Transfusion of 2 units of packed red cells

» Bleeding that occurred in an operated joint that required reoperation or intervention; or intramuscular bleeding with the compartment syndrome; or intracranial, intraspinal, intraocular, pericardial, or retroperitoneal bleeding


The ADOPT Trial: Results

In all, 6,528 acutely ill patients were randomized initially to receive short-term enoxaparin prophylaxis or extended apixaban prophylaxis. Approximately 2,000 patients were excluded for nonevaluable or missing lower extremity venous ultrasonograms during the 30-day treatment period.

The baseline characteristics of the patients in the two groups did not differ. The median age was 68 years in the apixaban arm and 67 years in the enoxaparin arm. Over 60% were > 65 years of age. About 80% were hospitalized for CHF or respiratory failure, with the remainder of patients hospitalized primarily for infectious causes without septic shock.



Data on 4,495 patients were analyzed for efficacy.

At 30 days, there were no significant difference between apixaban and enoxaparin in the primary efficacy outcome (2.71% vs 3.06%, respectively; RR, 0.87; 95% CI, 0.62–1.23; P = 0.44).

There was a significant increase in major bleeding in the apixaban arm compared with the enoxaparin arm (0.47% vs 0.19%; RR, 2.58; 95% CI, 1.04–7.24; P = 0.04).

This difference was likely due to the greater number of patients in the apixaban group who experienced a decrease in hemoglobin level 2 g/dL.



The key secondary outcome of VTE or death during the 6- to 14-day period prior to discontinuation of enoxaparin was also similar in both groups (1.73% vs 1.61%; RR, 1.06; 95% CI, 0.69–1.63).

There was a nonsignificant trend toward decreased symptomatic VTE and VTE-related mortality in patients treated with apixaban after enoxaparin therapy was discontinued (0.25% vs 0.58%; RR, 0.44; 95% CI, 0.19–1.00).

The primary driver of the difference was the decrease in symptomatic VTE among patients given extended thromboprophylaxis with apixaban when compared with those given enoxaparin (0.15% vs 0.49%).



Mortality in both groups of patients was 4.1%.

Within the early post-discharge period (< 14 days), when both groups received antithrombotic therapy, no patients died of VTE-related complications.

During the later follow-up period after enoxaparin therapy was stopped, there were two and three VTE-related deaths in the apixaban and enoxaparin arms, respectively.

The most common event over the 30-day treatment period was development of proximal DVT, which occurred in 2.4% of patients receiving apixaban and 2.5% receiving enoxaparin.


The ADOPT Trial: Discussion

Results regarding the primary endpoint of the ADOPT trial did not show a benefit from extended apixaban therapy when compared with enoxaparin use, but it did reveal a trend toward decreased symptomatic VTE and VTE-related deaths in the apixaban-treated group after discontinuation of enoxaparin therapy.

There were no differences in total bleeding events between the groups, but there was an increase in major bleeds in patients treated with apixaban.



The primary endpoint was underpowered due to the exclusion of approximately 2,000 patients for inadequate follow-up ultrasonography.

The comparator arm also was not representative of real-world practice, as treatment with enoxaparin for 6–14 days is not routine in post-discharge care.

Screening for DVT at 10 days post discharge is not routine; thus, the natural history and occurrence of VTE-related events likely were altered.

Although the overall findings were not statistically significant, there were many limitations to the final analysis:



The findings from the ADOPT trial do not support a strategy favoring extended-duration treatment with apixaban over short-term enoxaparin therapy in managing nonsurgical patients at high risk for developing VTE or PE post discharge.

A better understanding of the clinical factors that identify high-risk patients is necessary to balance the risk-benefit ratio.

The increased risk of bleeding seen in prior studies using enoxaparin and rivaroxaban for extended DVT prophylaxis also was observed in the ADOPT trial.



To date, the use of direct factor Xa inhibitors have not substantially mitigated the risk for bleeding when compared with enoxaparin therapy in the medically ill patient population.

However, with proper identification of patients at high risk for post-discharge DVT, both apixaban and rivaroxaban may yet have a role in this undertreated population.

Further, direct thrombin inhibitors offer the advantage of oral administration when compared with injected low-molecular-weight heparins and a more predictable dose response when compared with vitamin K antagonists such as warfarin.


Conclusion

Development of new direct inhibitors has focused primarily on direct factor Xa inhibitors, such as rivaroxaban and apixaban.

Whereas their safety profiles with regard to the occurrence of major bleeding have not been as robust as hoped, their clinical efficacy when compared with vitamin K antagonists and low-molecular-weight heparins has been well validated.

Because of their oral administration and few drug interactions, these novel anticoagulants may find new indications for short-term anticoagulant therapy in patients at high risk for thrombotic complications.


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© 2012 direct one communications, inc. all rights reserved. 1 the adopt trial and direct factor xa...

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